Compositions and methods for treating epilepsy

ABSTRACT

Compositions and methods for treating epilepsy and epileptic syndromes are described herein. The compositions and methods include therapeutically effective amounts of one or more dimebolins, or pharmaceutically acceptable salts thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 USC §119(e) to U.S.Provisional Application Ser. No. 61/096,940 filed on Sep. 15, 2008, andU.S. Provisional Patent Application Ser. No. 61/183,209 filed on Jun. 2,2009, the entire disclosure of each of which is incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to methods for treating epilepsy andepileptic syndromes. In particular, the invention relates to methods fortreating epilepsy and epileptic syndromes by administering atherapeutically effective amount of one or more dimebolins.

BACKGROUND AND SUMMARY OF THE INVENTION

Epilepsy is a common chronic neurological disorder that is characterizedby recurrent unprovoked seizures. These seizures may be transient signsand/or symptoms due to abnormal, excessive or synchronous neuronalactivity in the brain (Fisher et al., Epilepsia 46(4):470-2) (2005)).The foregoing publication, and each additional publication cited hereinis incorporated herein by reference.

In most studies, the overall incidence of epilepsy, with the exceptionof febrile convulsions and single seizures, in developed societies hasbeen found to be around 50 cases per 100,000 persons per year, but insome years as many as 70 per 100,000 have been reported. Surprising, thefigures for developing countries are generally higher, and range from100 to 190 per 100,000 each year. Though not confirmed, it has beensuggested that the higher occurrence may be due to social deprivation.For example, recent data suggest that people from socioeconomicallydeprived backgrounds in developed countries are more likely to developepilepsy.

The lifetime prevalence of seizures, namely, the risk of having anonfebrile epileptic seizure at some point in an average lifetime, isbetween 2 and 5%. In recent community based studies, it has been shownthat for most patients epilepsy is relatively short-lived; over twothirds enter long-term remission and once remission has occurred,subsequent relapses are uncommon. In fact, the course of the conditionin its early years is an important predictor of prognosis; the longerepilepsy remains active the poorer the long-term prognosis. Thecumulative incidence of febrile seizures, namely the risk of having afebrile seizure before the age of five, is about 5%, and febrileseizures account for a substantial proportion of seizures in childrenunder five.

Epileptic seizures typically involve excessive firing andsynchronization of neurons. This condition interrupts the normal workingof the parts of the brain involved, and in some cases leads to impairedconsciousness. Localization related epilepsies arise in the neocortexand limbic structures including the hippocampus and amygdala. Work on arange of experimental models produced detailed theories on thegeneration of brief (ca. 100-500 ms) epileptic events analogous to theinterictal spikes often found in the EEGs of humans with partialseizures. However, theories on full-blown seizures are less welldeveloped at present. Experimental interictal discharges are reportedlycharacterized by abrupt paroxysmal depolarization shifts that occursynchronously in the majority of neurons in the local area. Such largedepolarizations of 20-40 mV make the neurons fire rapid bursts of actionpotentials. In general, paroxysmal depolarization shifts have propertiesof a giant excitatory postsynaptic potential (EPSP), and depends onglutamate, the main excitatory synaptic transmitter in the brain. It hasbeen reported that it is the sum of simultaneous excitation from manyother neurons within the same population. In addition, contributionsfrom voltage sensitive calcium channels, which can produce slow actionpotentials, which may drive neurons above the threshold for the fastaction potentials, due to voltage sensitive sodium channels have beenimplicated.

Combined experimental and theoretical work on many experimental modelsshow that several features are necessary for this kind of epilepticdischarge. Excitatory (usually pyramidal) neurons must be connected intoa synaptic network. The probability of such connections can be as littleas 1-2% of randomly chosen pairs of pyramidal cells in the hippocampus.The synapses need to be strong enough, because of the properties of thesynapse and/or because of the firing pattern of the presynaptic neuron.For example, burst firing reportedly indicates that synaptic potentialscan be additive. Therefore, neurons need to have a good chance ofdriving their postsynaptic targets above threshold, and the populationof neurons must also be large enough, and constitute the minimumaggregate. This minimum aggregate allows neurons to connect with almostall the others in the population within a few synapses with the resultthat activity in a small subset of neurons can spread through thepopulation very rapidly under the right conditions. In experimentalmodels the minimum epileptic aggregate can be as low as 1000-2000neurons, but probably is larger in human epileptic foci. Acuteexperimental epilepsies, using convulsant treatments on normal braintissue, have been suggested to model symptomatic seizures.

Such acute experimental epilepsies may modify synaptic networks byseveral routes or combinations of routes. For example, synaptic networksmay be modified by blocking inhibitory synapses (using GABA as theirtransmitter) that normally control the excitation of the excitatorysynaptic network. This blocking is typical of many convulsants usedexperimentally, such as has been reported with pentylenetetrazol (PTZ)and bicuculline, and can occur clinically, such as has been reportedwith penicillin and quinolones, under certain conditions. Alternatively,or in combination, synaptic networks may be modified paradoxically. Forexample. excessive activation of GABA-A mediated synapses can switchthem from inhibitory to excitatory and thus promote epileptic activity.This effect may be due to a collapse of the gradient of chloride ionsacross the membrane, leaving bicarbonate ions as the main charge carrierat these synapses. Synaptic networks may be modified by strengtheningexcitatory synapses, for instance with abnormally low levels ofextracellular magnesium ions unblocking the NMDA subtype of glutamatereceptor, or by increasing neuronal excitability.

Other factors also contribute to epileptic discharges. Chronicexperimental models, and where it is possible to make the appropriatemeasurements in human localization related epilepsies, reveal multiplechanges which occur in various combinations in specific examples. Forexample, increased synaptic connectivity is a common feature, andperhaps most reported in mossy fibre sprouting, may promote the chainreaction recruitment of excitatory, glutamatergic neurons outlinedabove.

In addition, intrinsic properties are also involved. Voltage gated ionchannels change in many epilepsies, which may be profound in the smallminority of epilepsies that are genetic channelopathies. In some formsof epilepsy, potassium channels are weakened, while in others, sodiumchannels may become more persistent. In those cases the mutation ispresumably a primary factor in epileptogenesis. Changes in voltage gatedion channels also can be found in much more common epilepsies that donot have an obvious genetic basis, for instance temporal lobe epilepsywhere sodium channel inactivation is delayed (often in parallel with aloss of sensitivity to carbamazepine).

Synaptic receptors can also be different in epileptic tissue. Again theinherited channelopathies exhibit examples of altered GABAergicreceptors (tending to depress inhibitory potentials), and of changes innicotinic receptors. Other studies of more common idiopathic epilepsiesreveal alterations in expression of specific receptor subunits.

While interictal discharges have been reported as commonly associatedwith localization related epilepsy, it has been suggested that theyprobably are generated by different, or at least non-identical, circuitsfrom seizures. Moreover, their role in seizure generation is not wellunderstood, nor accepted. Results from some experimental models suggestthat interictal discharges may help prevent prolonged seizures gettingstarted, by mechanisms yet to be determined. Other studies suggest thatinterictal discharges may come in more than one variety, some of whichtend to precipitate seizures. Studies continue as to which factorsdetermine whether an epileptic discharge develops into a full-blownseizure. For example, it has been reported that during the first fewseconds of a seizure discharge, concentrations of extracellularpotassium ions increase from the normal of about 30-40 mM to a highlevel of greater than about 1000 mM, which in turn excites neurons, witha relatively slow time course. However, extracellular potassium appearsto accumulate too slowly to be the trigger for seizures, so themechanisms that sustain synchronous activity for the first few secondsmay be more important. The dynamics of the handling of extracellularpotassium and other neuroactive substances by neurons and glia duringseizures is also an active area of research.

It has been discovered that dimebolins, including dimebon itself (alsoknown as dimebolin hydrochloride) and analogs and derivatives thereof,as well as pharmaceutically acceptable salts of the foregoing, areuseful in treating patients suffering from or in need of relief fromepilepsy and/or epileptic syndromes.

In one illustrative embodiment of the invention, methods for treatingepilepsy are described. In another illustrative embodiment of theinvention, methods for treating epileptic syndromes are described. Ineach of the foregoing, the methods include the step of administering atherapeutically effective amount of one or more dimebolins, and/orpharmaceutically acceptable salts thereof, to a patient suffering from,or in need of relief from epilepsy and/or epileptic syndrome. In anotherembodiment, methods are described herein that include the step ofadministering a therapeutically effective amount of one or moredimebolins, and/or pharmaceutically acceptable salts thereof, andadministering a therapeutically effective amount of one or more NMDAreceptor antagonists to a patient suffering from, or in need of relieffrom epilepsy and/or epileptic syndrome. In another embodiment, methodsare described herein that include the step of administering atherapeutically effective amount of one or more dimebolins, and/orpharmaceutically acceptable salts thereof, and administering atherapeutically effective amount of one or more AMPA receptorantagonists to a patient suffering from, or in need of relief fromepilepsy and/or epileptic syndrome. In another embodiment, methods aredescribed herein that include the step of administering atherapeutically effective amount of one or more dimebolins, and/orpharmaceutically acceptable salts thereof, and administering atherapeutically effective amount of one or more additionalanti-epileptic drugs to a patient suffering from, or in need of relieffrom epilepsy and/or epileptic syndrome. In another embodiment, methodsare described herein that include the step of administering atherapeutically effective amount of one or more dimebolins, and/orpharmaceutically acceptable salts thereof, administering atherapeutically effective amount of one or more NMDA receptorantagonists, and administering a therapeutically effective amount of oneor more additional anti-epileptic drugs to a patient suffering from, orin need of relief from epilepsy and/or epileptic syndrome.

In another illustrative embodiment of the invention, uses of dimebolinsand pharmaceutically acceptable salts thereof in the manufacture ofmedicaments for treating epilepsy and epileptic syndromes are described.In each of the foregoing, the medicaments include a therapeuticallyeffective amount of one or more dimebolins, and/or pharmaceuticallyacceptable salts thereof. In another embodiment, the medicaments includea therapeutically effective amount of one or more dimebolins, and/orpharmaceutically acceptable salts thereof, and a therapeuticallyeffective amount of one or more NMDA receptor antagonists. In anotherembodiment, the medicaments include a therapeutically effective amountof one or more dimebolins, and/or pharmaceutically acceptable saltsthereof, and a therapeutically effective amount of one or more AMPAreceptor antagonists. In another embodiment, the medicaments include atherapeutically effective amount of one or more dimebolins, and/orpharmaceutically acceptable salts thereof, and a therapeuticallyeffective amount of one or more additional anti-epileptic drugs. Inanother embodiment, the medicaments include a therapeutically effectiveamount of one or more dimebolins, and/or pharmaceutically acceptablesalts thereof, a therapeutically effective amount of one or more NMDAreceptor antagonists, and a therapeutically effective amount of one ormore additional anti-epileptic drugs.

In another embodiment, the methods described herein include theco-administration of a therapeutically effective amount of one or morestatins. It is to be understood that the one or more statins may beco-administered in each of the foregoing embodiments, and otherembodiments described herein, including but not limited toco-administration with one or more dimebolins, co-administration withone or more dimebolins and NMDA antagonists, co-administration with oneor more dimebolins, NMDA antagonists, and other anti-epileptic drugs,and the like.

In another illustrative embodiment, pharmaceutical compositions aredescribed herein. Illustrative pharmaceutical compositions includevarious dosage forms of dimebolins and/or pharmaceutically acceptablesalts thereof in combination with one or more pharmaceuticallyacceptable carriers, excipients, and/or diluents therefor. Otherillustrative pharmaceutical compositions include various dosage forms of(a) one or more dimebolins and one or more NMDA antagonists, includingmixtures thereof; (b) one or more dimebolins and one or more and one ormore other anti-epileptic drugs, including mixtures thereof; (c) one ormore dimebolins, one or more and one or more other anti-epileptic drugs,and one or more NMDA antagonists, including mixtures thereof; and (d)any of the foregoing also including one or more statins, includingmixtures thereof. In each of the foregoing, it is to be understood thatpharmaceutically acceptable salts of any of the dimebolins, NMDAantagonists, other anti-epileptic drugs, and/or statins, and the likeare included. It is also to be understood that the dosage formsdescribed herein that include mixtures, also include sandwich-typeformulations where two or more separate drug dosage forms are adheredone to the other for simultaneous co-administration.

In another illustrative embodiment, kits and packages are describedherein. Illustrative kits and packages include preparations where thecompounds are adapted for co-administered, such as being placed in aformat following the dosing protocols described herein. For example, anillustrative package may include a grid pattern, wherein each sectionincludes a dual bubble pack for the dimebolin dosage and illustrativelythe NMDA antagonist dosage. It is appreciated that other configurationsthat include the anti-epileptic drug, or both the NMDA antagonist andanti-epileptic drug, or alternatively a statin are also describedherein.

DETAILED DESCRIPTION

Dimebolins are known antihistamine drugs. In particular, dimebolinhydrochloride has been used clinically for many years (Matveeva,Farmakologiia i Toksikologiia, 46(4):27-29 (July-August 1983)), and hasrecently shown potential in the treatment of Alzheimer's disease (Doodyet al., Lancet 372:207-215 (2008)). However, the beneficial use ofdimebolins in treating epilepsy has heretofore been unknown. Withoutbeing bound by theory, it is believed herein that dimebolins may exerttheir actions in treating epilepsy and epileptic syndromes via multiplemechanisms. Illustratively, it has been discovered herein that theutility of dimebolins for treating epilepsy and epileptic syndromes mayarise from one or more of its abilities to modulate the activity of AMPAand/or NMDA glutamate receptors (Grigorev et al., Bull Exp Biol Med.,136(5):474-477 (2003)), inhibit L-type calcium channels (Lermontova etal., Bulletin of Experimental Biology and Medicine, 132(5):1079-83(2001)), block the action of neurotoxic beta-amyloid proteins, and/orblock mitochondrial permeability transition pores (Bachurin et al.,Annals of the New York Academy of Sciences, 993:334-344 (2003)), whichare believed to play a role in the cell death that is associated withcertain neurodegenerative diseases and aging in general. In particular,it is believed herein that glutamate receptors may play an importantrole in seizure initiation, maintenance and arrest. However, it isappreciated that blockade of all NMDA sites may have several unwantedside effects, such as has been observed with PCP narcotics. It isunderstood that retaining activity at selective and/or specific subunitsis advantageous while at the same time modulating the activity ofcertain other AMPA and/or NMDA glutamate receptors.

In addition, compounds that have accompanying biochemical action maymitigate the effects of NMDA antagonism. For example, it has beendiscovered herein that dimebolins inhibit mitochrondrial permeabilitytransition pores, and therefore may lead to protection of mitochondriafrom degradation.

Without being bound by theory, it is suggested that the anti-epilepticpotential of a method of treatment or a pharmaceutical composition thatincludes one or more dimebolins, and/or pharmaceutically acceptablesalts thereof, is not exclusively related to their anti-NMDA and/or NMDAantagonist activity. For example, a well known NMDA receptor antagonistis 2-amino-5-phosphonovaleric acid (AP5 or APV) (Evans et al., Brit. J.Pharmacol., 1982, v.75, p.65), and yet, AP5 has been reported to sufferfrom the disadvantage of having neurotoxic effects, includingdisturbance of coordination of movement and a sedative effect, each ofwhich becomes apparent when AP5 is used in the doses in which itproduces its anti-NMDA effect (ED₅₀=190 mg/kg, Grigoriev et al. Chim.Pharm. Journal, 1988, No. 3, p. 275-277). Accordingly, but without beingbound by theory, it is believed herein that dimebolins exert selectiveaction on NMDA sites. For example, dimebolins reportedly affect thepolyamine site of NMDA-receptor located on the NR2B subunit, which isalso the target for histamine (Grigorev et al., Bull Exp Biol Med,136(5):474-7 (2003)). In addition, it has been reported that theH1-histamine receptor antagonist activity of dimebolins may also exert amodulating activity of NMDA-receptors by binding to that site. Thus, ithas been discovered herein that the effect of dimebolins in lowconcentrations may be most pronounced in neuronal populations with highconcentration of NR2B subunits. Such neuronal populations are primarilyfound in the fronto-parieto-temporal cortex and hippocampus pyramidalcells. It is understood herein that the temporal cortex and hippocampusare involved in the development of epilepsy, mainly of the temporal lobesubtype (McIntyre D C, et al. Epilepsia, 49 Suppl 3:23-30 (2008)).

It is also appreciated herein that epileptic activity results in Ca²⁺ion-dependent changes in mitochondrial function that might contribute tothe neuronal injury induced by epilepsy (Kovács R, et al., J Neurosci.,25(17):4260-9 (2005)). Without being bound by theory, it is alsobelieved herein that the efficacy of dimebolins may be due at least inpart to their ability to block L-type calcium channels. Further, butwithout being bound by theory, it is believed herein that the efficacyof dimebolins may be due at least in part to their ability to inhibitmitochondrial permeability transition, a process involved incalcium-induced neurotoxicity, and can therefore be beneficial in thetreatment of epilepsy. It is believed herein that inhibition ofmitochondrial permeability transition pores decreases the damage causedduring an epileptic seizure, especially the damage to cognitive functionthat may result.

Without being bound by theory, it is also believed herein that thepharmacokinetic characteristics and blood-brain-barrier permeability ofdimebolins, in conjunction with a low number of adverse events reportedin other therapies, are useful in treating epilepsy and epilepticsyndromes according to the methods described herein. In contrast, manyother NMDA antagonists have limited potential due at least in part to anunacceptable adverse prevent profile, such as has been reported fortreatments including Aptiganel, Phencyclidine, and remacemide,unfavorable pharmacokinetic characteristics, such as with MRZ 2/596 andMDL 105,519, or reduced efficacy, such as with remacemide.

As used herein, the term “dimebolin” generally refers to the compoundsdescribed herein and analogs and derivatives thereof. It is also to beunderstood that in each of the foregoing, any correspondingpharmaceutically acceptable salt is also included in the illustrativeembodiments described herein. Illustrative derivatives include, but arenot limited to, both those compounds that may be synthetically preparedfrom the compounds described herein, as well as those compounds that maybe prepared in a similar way as those described herein, but differing inthe selection of starting materials. For example, described herein areillustrative dimebolins of formulae (I), (II), and (III) that includevarious functional groups on aromatic rings, such as R³. It is to beunderstood that derivatives of those compounds also include thecompounds having for example different functional groups on thosearomatic rings than those explicitly set forth in the definition offormulae (I), (II), and (III). In addition, it is to be understood thatderivatives of those compounds also include the compounds having thosesame or different functional groups at different positions on thearomatic ring. Similarly, derivatives include parallel variations ofother functional groups on the compounds described herein, such as R¹,and the like.

Illustrative analogs include, but are not limited to, those compoundsthat share functional and in some cases structural similarity to thosecompounds described herein. For example, described herein areillustrative dimebolins of formulae (I), (II), and (III) that include a2,3,4,5-tetrahydro-1H-pyridoindole ring system. Illustrative analogsinclude, but are not limited to, the corresponding ring expandedcompounds, such as the corresponding azepinoindole ring system, and thelike. Other illustrative analogs include, but are not limited to, thecorresponding ring systems that include additional heteroatoms, such asthe corresponding pyridazinoindole ring system, and the like.

Without being bound by theory, it is believed herein that oneillustrative characteristic of the dimebolins, including analogs of thecompounds described herein, is NMDA antagonism coupled with the abilityto block L-type calcium channels. Without being bound by theory, it isbelieved herein that another illustrative characteristic of dimebolins,including analogs of the compounds described herein, is MPTP inhibition.

In addition, as used herein the term dimebolins also refers to prodrugderivatives of the compounds described herein, and including prodrugs ofthe various analogs and derivatives thereof. The term “prodrug” as usedherein generally refers to any compound that when administered to abiological system generates a biologically active compound as a resultof one or more spontaneous chemical reaction(s), enzyme-catalyzedchemical reaction(s), and/or metabolic chemical reaction(s), or acombination thereof. In vivo, the prodrug is typically acted upon by anenzyme (such as esterases, amidases, phosphatases, and the like), simplebiological chemistry, or other process in vivo to liberate or regeneratethe more pharmacologically active drug. This activation may occurthrough the action of an endogenous host enzyme or a non-endogenousenzyme that is administered to the host preceding, following, or duringadministration of the prodrug. Additional details of prodrug use aredescribed in U.S. Pat. No. 5,627,165; and Pathalk et al., Enzymicprotecting group techniques in organic synthesis, Stereosel. Biocatal.775-797 (2000). It is appreciated that the prodrug is advantageouslyconverted to the original drug as soon as the goal, such as targeteddelivery, safety, stability, and the like is achieved, followed by thesubsequent rapid elimination of the released remains of the groupforming the prodrug.

Prodrugs may be prepared from the compounds described herein byattaching groups that ultimately cleave in vivo to one or morefunctional groups present on the compound, such as —OH—, —SH, —CO₂H,—NR₂. Illustrative prodrugs include but are not limited to carboxylateesters where the group is alkyl, aryl, aralkyl, acyloxyalkyl,alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amineswhere the group attached is an acyl group, an alkoxycarbonyl,aminocarbonyl, phosphate or sulfate. Further illustrative prodrugscontain a chemical moiety, such as an amide or phosphorus groupfunctioning to increase solubility and/or stability of the compoundsdescribed herein. Further illustrative prodrugs for amino groupsinclude, but are not limited to, (C₃-C₂₀)alkanoyl;halo-(C₃-C₂₀)alkanoyl; (C₃-C₂₀)alkenoyl; (C₄-C₇)cycloalkanoyl;(C₃-C₆)-cycloalkyl(C₂-C₁₆)alkanoyl; optionally substituted aroyl, suchas unsubstituted aroyl or aroyl substituted by 1 to 3 substituentsselected from the group consisting of halogen, cyano,trifluoromethanesulphonyloxy, (C₁-C₃)alkyl and (C₁-C₃)alkoxy, each ofwhich is optionally further substituted with one or more of 1 to 3halogen atoms; optionally substituted aryl(C₂-C₁₆)alkanoyl, such as thearyl radical being unsubstituted or substituted by 1 to 3 substituentsselected from the group consisting of halogen, (C₁-C₃)alkyl and(C₁-C₃)alkoxy, each of which is optionally further substituted with 1 to3 halogen atoms; and optionally substituted heteroarylalkanoyl havingone to three heteroatoms selected from O, S and N in the heteroarylmoiety and 2 to 10 carbon atoms in the alkanoyl moiety, such as theheteroaryl radical being unsubstituted or substituted by 1 to 3substituents selected from the group consisting of halogen, cyano,trifluoromethanesulphonyloxy, (C₁-C₃)alkyl, and (C₁-C₃)alkoxy, each ofwhich is optionally further substituted with 1 to 3 halogen atoms. Thegroups illustrated are exemplary, not exhaustive, and may be prepared byconventional processes.

It is understood that the prodrugs themselves may not possesssignificant biological activity, but instead undergo one or morespontaneous chemical reaction(s), enzyme-catalyzed chemical reaction(s),and/or metabolic chemical reaction(s), or a combination thereof afteradministration in vivo to produce the compound described herein that isbiologically active or is a precursor of the biologically activecompound. However, it is appreciated that in some cases, the prodrug isbiologically active. It is also appreciated that prodrugs may oftenserves to improve drug efficacy or safety through improved oralbioavailability, pharmacodynamic half-life, and the like. Prodrugs alsorefer to derivatives of the compounds described herein that includegroups that simply mask undesirable drug properties or improve drugdelivery. For example, one or more compounds described herein mayexhibit an undesirable property that is advantageously blocked orminimized may become pharmacological, pharmaceutical, or pharmacokineticbarriers in clinical drug application, such as low oral drug absorption,lack of site specificity, chemical instability, toxicity, and poorpatient acceptance (bad taste, odor, pain at injection site, and thelike), and others. It is appreciated herein that a prodrug, or otherstrategy using reversible derivatives, can be useful in the optimizationof the clinical application of a drug.

In addition, as used herein, the term dimebolins refers to both theamorphous as well as any and all morphological forms of each of thecompounds described herein. In addition, as used herein, the termdimebolins refers to any and all hydrates, or other solvates, of thecompounds described herein.

As used herein, the term “epilepsy” includes neurological disorders thatare characterized by recurrent seizures. Such seizures may be transientsigns and/or symptoms that arise due to abnormal, excessive orsynchronous neuronal activity in the brain. Illustrative examples ofepileptic seizures treatable with the methods and medicaments describedherein include, but are not limited to, tonic-clonic, clonic (with orwithout tonic features), absence (typical or atypical), myoclonicabsence, tonic, myoclonic, massive bilateral myoclonus, negativemyoclonus, eyelid myclonia (accompanied or not by absence seizures),myoclonic-atonic, atonic, reflex, focal sensory (with elementary sensorysymptoms, such as occipital and parietal lobe seizures, or experientialsensory symptoms, such as temporo parieto occipital junction seizures,and the like), focal motor (with elementary clonic motor signs, withasymmetrical tonic motor signs or seizure, such as supplementary motorseizures, with typical automatisms, also referred to as temporal lobeautomatisms, such as mesial temporal lobe seizures, with hyperkineticautomatisms, with focal negative myoclonus, and the like), inhibitorymotor, gelastic, hemiclonic, secondarily generalized, reflex seizures infocal epilepsy syndromes, generalized tonic-clonic status epilepticus,clonic status epilepticus, absence status epilepticus, tonic statusepilepticus, myoclonic status epilepticus, epilepsia partialis continua,aura continua, limbic status epilepticus, hemiconvulsive statusepilepticus.

It is appreciated that epilepsy may also occur in the context of one ormore epileptic syndromes. Illustrative examples of epileptic syndromestreatable with the methods and medicaments described herein include, butare not limited to, benign familial neonatal seizures, early myoclonicencephalopathy, Ohtahara syndrome, migrating partial seizures ofinfancy, West syndrome, benign myoclonic epilepsy in infancy, benignfamilial and non-familial infantile seizures, Dravet's syndrome, HHsyndrome, myoclonic status in nonprogressive encephalopathies, benignchildhood epilepsy with centrotemporal spikes, early onset benignchildhood occipital epilepsy (Panayiotopoulos type), late onsetchildhood occipital epilepsy (Gastaut type), epilepsy with myoclonicabsences, epilepsy with myoclonic-astatic seizures, Lennox-Gastautsyndrome, Landau-Kleffner syndrome, epilepsy with continuousspike-and-waves during slow-wave sleep (other than LKS), childhoodabsence epilepsy, progressive myoclonus epilepsies, idiopathicgeneralized epilepsies with variable phenotypes (juvenile absenceepilepsy, juvenile myoclonic epilepsy), reflex epilepsies, idiopathicphotosensitive occipital lobe epilepsy, visual sensitive epilepsies,primary reading epilepsy, startle epilepsy, autosomal dominant nocturnalfrontal lobe epilepsy, familial temporal lobe epilepsies, generalizedepilepsies with febrile seizures plus, familial focal epilepsy withvariable foci, limbic epilepsies, mesial temporal lobe epilepsy withhippocampal sclerosis, mesial temporal lobe epilepsy defined by specificetiologies, other types defined by location and etiology, neocorticalepilepsies, Rasmussen syndrome, benign neonatal seizures, febrileseizures, reflex seizures, alcohol withdrawal seizures, drug or otherchemically-induced seizures, immediate and early post traumaticseizures, single seizures or isolated clusters of seizures, and rarelyrepeated seizures (oligo-epilepsy).

In another embodiment, methods are described herein for treatingJuvenile Myoclonic Epilepsy that include the step of administering atherapeutically effective amount of one or more dimebolins orpharmaceutically acceptable salts thereof. In another embodiment,methods are described herein for treating Juvenile Myoclonic Epilepsythat include the step of co-administering a therapeutically effectiveamount of one or more dimebolins or pharmaceutically acceptable saltsthereof with a therapeutically effective amount of another subtypeselective or subtype specific NMDA antagonists. In another embodiment,methods are described herein for treating Juvenile Myoclonic Epilepsythat include the step of co-administering a therapeutically effectiveamount of one or more dimebolins or pharmaceutically acceptable saltsthereof with a therapeutically effective amount of one or moreinhibitors of HMG-CoA reductase, also referred to as statins. In anotherembodiment, methods are described herein for treating Juvenile MyoclonicEpilepsy that include the step of co-administering a therapeuticallyeffective amount of one or more dimebolins or pharmaceuticallyacceptable salts thereof with one or more GABA transaminase inhibitors.In another embodiment, methods are described herein for treatingJuvenile Myoclonic Epilepsy that include the step of co-administering atherapeutically effective amount of one or more dimebolins orpharmaceutically acceptable salts thereof with one or more T-TypeCalcium Channel inhibitors. In another embodiment, methods are describedherein for treating Juvenile Myoclonic Epilepsy that include the step ofco-administering a therapeutically effective amount of one or moredimebolins or pharmaceutically acceptable salts thereof with one or morestatins and one or more GABA transaminase inhibitors.

In another embodiment, methods are described herein for treatingepilepsy or epileptic syndromes that include the step of administering atherapeutically effective amount of one or more dimebolins of formula(I)

or a pharmaceutically acceptable salt thereof, wherein R¹ is alkyl orarylalkyl; R² is hydrogen, benzyl, or 6-methylpyridinyl-3-ethyl; R³ ishydrogen, alkyl, or halo; and bond (a) is a single bond or a doublebond.

In another embodiment, methods are described herein that include thestep of administering a therapeutically effective amount of a dimebolinof formula (I) wherein R¹ is methyl, ethyl or benzyl. In anotherembodiment, methods are described herein that include the step ofadministering a therapeutically effective amount of a dimebolin offormula (I) wherein R² is hydrogen, benzyl, or6-methylpyridinyl-3-ethyl. In another embodiment, methods are describedherein that include the step of administering a therapeuticallyeffective amount of a dimebolin of formula (I) wherein R³ is hydrogen,methyl, or bromo.

In another embodiment, methods are described herein for treatingepilepsy and epileptic syndromes that include the step of administeringa therapeutically effective amount of a dimebolin of formula (I) whereinbond (a) is a single bond; R¹ and R³ are each methyl; and R² ishydrogen. In another embodiment, methods are described herein thatinclude the step of administering a therapeutically effective amount ofa dimebolin of formula (I) wherein bond (a) is a single bond; and thering fusion is cis. In another embodiment, methods are described hereinthat include the step of administering a therapeutically effectiveamount of a dimebolin of formula (I) wherein bond (a) is a double bond;R¹ is ethyl or benzyl; and R² and R³ are each hydrogen; or R¹ and R³ areeach methyl; and R² is benzyl; or R¹ is methyl; R² is6-methylpyridinyl-3-ethyl; and R³ is hydrogen; or R¹ and R³ are eachmethyl; and R² is 6-methylpyridinyl-3-ethyl; or R¹ is methyl; R² ishydrogen; and R³ is hydrogen or methyl; or R¹ is methyl; R² is hydrogen;and R³ is bromo.

In another embodiment, methods are described herein for treatingepilepsy and epileptic syndromes that include the step of administeringa therapeutically effective amount of one or more dimebolins of formula(II)

or a pharmaceutically acceptable salt thereof, wherein R¹ is alkyl orarylalkyl; R² is hydrogen, benzyl, or 6-methylpyridinyl-3-ethyl; R³ ishydrogen, alkyl, or halo; and bond (a) is a single bond or a doublebond.

In another embodiment, methods are described herein for treatingepilepsy and epileptic syndromes that include the step of administeringa therapeutically effective amount of a dimebolin of formula (II)wherein R¹ is methyl, ethyl or benzyl. In another embodiment, methodsare described herein that include the step of administering atherapeutically effective amount of a dimebolin of formula (II) whereinR² is hydrogen, benzyl, or 6-methylpyridinyl-3-ethyl. In anotherembodiment, methods are described herein that include the step ofadministering a therapeutically effective amount of a dimebolin offormula (II) wherein R³ is hydrogen, methyl, or bromo. In anotherembodiment, methods are described herein include the step ofadministering a therapeutically effective amount of a dimebolin offormula (II) wherein R¹ and R³ are each methyl; and R² is hydrogen. Inanother embodiment, methods are described herein that include the stepof administering a therapeutically effective amount of a dimebolin offormula (II) wherein the ring fusion is cis. In another embodiment,methods are described herein that include the step of administering atherapeutically effective amount of a dimebolin of formula (II) in apharmaceutically acceptable quaternary salt form.

In another embodiment, methods are described herein for treatingepilepsy and epileptic syndromes that include the step of administeringa therapeutically effective amount of one or more dimebolins of formula(III)

or a pharmaceutically acceptable salt thereof, wherein R¹ is alkyl orarylalkyl; R² is hydrogen, benzyl, or 6-methylpyridinyl-3-ethyl; R³ ishydrogen, alkyl, or halo; and bond (a) is a single bond or a doublebond.

In another embodiment, methods are described herein for treatingepilepsy and epileptic syndromes that include the step of administeringa therapeutically effective amount of one or more dimebolins of formula(III) wherein R¹ is methyl, ethyl or benzyl. In another embodiment,methods are described herein that include the step of administering atherapeutically effective amount of one or more dimebolins of formula(III) wherein R² is hydrogen, benzyl, or 6-methylpyridinyl-3-ethyl. Inanother embodiment, methods are described herein that include the stepof administering a therapeutically effective amount of one or moredimebolins of formula (III) wherein R³ is hydrogen, methyl, or bromo.

In another embodiment, methods are described herein for treatingepilepsy and epileptic syndromes that include the step of administeringa therapeutically effective amount of one or more dimebolins of formula(III) wherein R¹ is ethyl or benzyl; and R² and R³ are each hydrogen; orR¹ and R³ are each methyl; and R² is benzyl; or R¹ is methyl; R² is6-methylpyridinyl-3-ethyl; and R³ is hydrogen; or R¹ and R³ are eachmethyl; and R² is 6-methylpyridinyl-3-ethyl; or R¹ is methyl; R² ishydrogen; and R³ is hydrogen or methyl; or R¹ is methyl; R² is hydrogen;and R³ is bromo. In another embodiment, methods are described hereinthat include the step of administering a therapeutically effectiveamount of one or more dimebolins of formula (III) in a pharmaceuticallyacceptable quaternary salt form.

In another embodiment, methods are described herein for treatingepilepsy and epileptic syndromes that include the step of administeringa therapeutically effective amount of a dimebolin of the formula

or a pharmaceutically acceptable salt, such as the hydrochloride salt.

In another embodiment, methods are described herein for treatingepilepsy and epileptic syndromes that include the step of administeringa therapeutically effective amount of one or more compounds selectedfrom 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, or itsmethyliodide; cis-(±)2,8-dimethyl-2,3,4,4a,5,9b-hexahydro1H-pyrido[4,3-b]indole, or itsdihydrochloride;2-methyl-8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, or itshydrochloride; 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;2,8-dimethyl-5-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, or itshydrochloride;2-methyl-5-[2-(6-methyl-3-pyridyl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole,or its sesquisulfate monohydrate; and2,8-dimethyl-5-[2-(6-methyl-3-pyridyl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole,or its dihydrochloride. The foregoing compounds may be preparedaccording to Horlein, Chem. Ber., 1954, Bd.87, hft 4, p. 463-472;Cattanach et al., J. Chem. Soc. (ser. C) 1968, 1235-1243; Yurovskaya andRodionov, Khim. Geterots. Soed., 1981, No. 8, p. 1072-1078; Yakhontovand Glushkova, Synthatic Drugs (edited by A. G. Natradze), Moscow,“Meditsina Publishers”, 1983, p. 234-237; Buu-Hoi et al., J. Chem. Soc.,1964, No. 2, p. 708-711; Kucherova and Kochetkov, J. Obshch. Khim.,1956, v. 26, p. 3149-3154; and Kost et al., “Khim. Geterots. Soed.”,1973, No. 2, p. 207-212, the disclosure of which are incorporated hereinby reference.

In another embodiment, one or more dimebolins or pharmaceuticallyacceptable salts thereof is co-administered with another NMDAantagonist, such as a subtype selective or subtype specific NMDAantagonist. In another embodiment, one or more dimebolins orpharmaceutically acceptable salts thereof is co-administered withanother AMPA antagonist, such as a subtype selective or subtype specificAMPA antagonist. Glutamate receptors bind glutamate, an excitatory aminoacid neurotransmitter. Upon binding glutamate, the receptors facilitatethe flow of both sodium and calcium ions into the cell, while potassiumions flow out of the cell, resulting in excitation. The glutamatereceptor has 5 potential binding sites and causes different responsesdepending on the stimulated or blocked site. These sites are thealpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) site,the kainate site, the N-methyl-D-aspartate (NMDA) site, the glycinesite, and the metabotropic site that has 7 subunits (GluR 1-7). AEDsthat modify these receptors are antagonistic to glutamate.

Illustrative NMDA antagonists include, but are not limited toamantadine, dextromethorphan, dextrorphan, ibogaine, ketamine,phencyclidine, riluzole, tiletamine. memantine (also known as AXURA,AKATINOL, NAMENDA, EBIXA, and 1-amino-3,5-dimethylada-mantane). Inanother embodiment, one or more dimebolins or pharmaceuticallyacceptable salts thereof is co-administered with one or more ofriluzole, memantine, and dextromethorphan, and therapeutically activeand pharmaceutically acceptable salt derivatives thereof, including acidaddition salt forms. In another embodiment, one or more dimebolins orpharmaceutically acceptable salts thereof is co-administered withmemantine.

In another embodiment, one or more dimebolins or pharmaceuticallyacceptable salts thereof is co-administered with another NMDAantagonist, such as an noncompetitive antagonist, including but notlimited to Dizocilpine (also known as MK-801), aptiganel (also known asCERESTAT, CNS-1102), remacimide, and HU-211. In another embodiment, oneor more dimebolins or pharmaceutically acceptable salts thereof isco-administered with HU-211.

In another embodiment, one or more dimebolins or pharmaceuticallyacceptable salts thereof is co-administered with another NMDAantagonist, such as a glycine antagonist that acts at the glycinebinding site, including but not limited to 7-chlorokynurenate,5,7-dichlorokynurenic acid (DCKA), kynurenic acid, and1-aminocyclopropanecarboxylic acid (ACPC).

In another embodiment, one or more dimebolins or pharmaceuticallyacceptable salts thereof is co-administered with another NMDAantagonist, such as a competitive antagonist, including but not limitedto 2-amino-7-phosphonoheptanoic acid (AP7),R-2-amino-5-phosphonopentanoate (APV), and CPPene(3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid).

In another embodiment, one or more dimebolins or pharmaceuticallyacceptable salts thereof is co-administered with another anti-epilepticdrug (AED). Illustrative AEDs may be grouped according to their mainmechanism of action, although it is to be understood that such aclassification is not be interpreted as limiting because many AEDs havebeen reported to operate by more than one mode of action. The majorityof modes of action reported as possible bases of the efficacy of AEDs,include sodium channel blockers, calcium current inhibitors,gamma-aminobutyric acid (GABA) enhancers, glutamate blockers, carbonicanhydrase inhibitors, and hormones (Ochoa et al., “Antiepileptic Drugs:An Overview” emedicine from WebMD (Apr. 17, 2009)).

Illustrative anti-epileptic drugs include, but are not limited toacetazolamide, acetazolamide modified release, barbexaclone,breveracetam, carbamazepine, carbamazepine modified release, clobazam,clonazepam, clorazepate, diazepam, ethosuximide, ethotoin, felbamate,gabapentin, lamotrigine, levetiracetam, lorazepam, mephenytoin,mesuximide, methazolamide, methylphenobarbital, oxcarbamazepine,phenobarbital (phenobarbitone), phensuximide, phenytoin, pregabalin,primidone, progabide, seletracetam, rufinamide, valproic acid, sodiumvalproate, divalproate sodium, sodium valproate modified release,tiagabine, topiramate, vigabatrin, and zonisamide, including sustainedreleased zonisamide.

In another embodiment, one or more dimebolins or pharmaceuticallyacceptable salts thereof is co-administered with a voltage-gated sodiumchannel antagonist, such as with oxcarbamazepine. For example, it hasbeen reported that the firing of an action potential by an axon isaccomplished through sodium channels. Each sodium channel dynamicallyexists in 3 states, as follows: a resting state during which the channelallows passage of sodium into the cell; an active state in which thechannel allows increased influx of sodium into the cell; and an inactivestate in which the channel does not allow passage of sodium into thecell. During an action potential, these channels exist in the activestate and allow influx of sodium ions. Once the activation or stimulusis terminated, a percentage of these sodium channels become inactive fora period of time known as the refractory period. With constant stimulusor rapid firing, many of these channels exist in the inactive state,rendering the axon incapable of propagating the action potential. AEDsthat target these sodium channels may prevent the return of thesechannels to the active state by stabilizing the inactive form of thesechannels. In doing so, repetitive firing of the axons is prevented.

In another embodiment, one or more dimebolins or pharmaceuticallyacceptable salts thereof is co-administered with a voltage-dependentcalcium channel blockers, such as an L-type channel blocker.Illustrative calcium channel blockers include, but are not limited to,oxcarbamazepine. While the mode of action of several AEDs includes themodification of glutamate receptors (Sierra-Paredes and Sierra-Marcuno,Extrasynaptic GABA and glutamate receptors in epilepsy, CNS NeurolDisord Drug Targets, 6(4):288-300 (2007); Nateri et al., EMBO J., 2007Nov. 28, 26(23):4891-901 Epub 2007 Nov. 1)), inhibition ofvoltage-dependent calcium channels (VDCC) has been reported to mediatethe effects of those and other AEDs. Calcium channels have been reportedto exist in 3 known forms in the human brain, namely the L, N, and Tforms. These channels are small and are inactivated quickly. The influxof calcium currents in the resting state produces a partialdepolarization of the membrane, facilitating the development of anaction potential after rapid depolarization of the cell. They functionas the pacemakers of normal rhythmic brain activity. This is trueparticularly of the thalamus. T-form calcium channels have been known toplay a role in the 3 per second spike-and-wave discharges of absenceseizures. Anti-epileptic drugs that inhibit these T-calcium channelshave been reported to be particularly useful for controlling absenceseizures.

In another embodiment, one or more dimebolins or pharmaceuticallyacceptable salts thereof is co-administered with a GABA mimetic or GABAagonist. Illustrative GABA mimetics include, but are not limited totiagabine, vigabatrin, and the like. Without being bound by theory, itis believed herein that when GABA binds to a GABA-A receptor, thepassage of chloride, a negatively charged ion, into the cell isfacilitated via chloride channels. This influx of chloride increases thenegativity of the cell, resulting in a more negative resting membranepotential. This negativity causes the cell to have greater difficultyreaching the action potential. GABA is produced by decarboxylation ofglutamate mediated by the enzyme glutamic acid decarboxylase (GAD).Certain AEDs have been reported to act as modulators of this enzyme,enhancing the production of GABA and down-regulating glutamate. OtherAEDs may function as an agonist to this mode of chloride conductance byblocking the reuptake of GABA, such as the drug tiagabine, oralternatively by inhibiting its metabolism mediated by GABAtransaminase, such as the drug vigabatrin, resulting in increasedaccumulation of GABA at the postsynaptic receptors.

In another embodiment, methods are described herein for treatingepilepsy and epileptic syndromes that include the step ofco-administering a therapeutically effective amount of one or moredimebolins or pharmaceutically acceptable salts thereof with one or moreGABA transaminase inhibitors. In another embodiment, methods aredescribed herein that include the step of co-administering atherapeutically effective amount of one or more dimebolins orpharmaceutically acceptable salts thereof with one or more T-TypeCalcium Channel inhibitors.

Other AEDs have been reported to exert efficacy by inhibition of theenzyme carbonic anhydrase, which increases the concentration of hydrogenions intracellularly and decreases the pH. The potassium ions shift tothe extracellular compartment to buffer the acid-base status. This eventresults in hyperpolarization and an increase in seizure threshold of thecells. Acetazolamide, an inhibitor of carbonic anhydrase, has been usedas an adjunctive therapy in refractory seizures with catamenial pattern,such as seizure clustering around menstrual period. Topiramate andzonisamide also are weak inhibitors of this enzyme; however, thatactivity is not believed to be an important mechanism for their observedantiseizure efficacy. Other AEDs have been reported to mimic theactivity of certain sex hormones. For example, progesterone is a naturalanticonvulsant that acts by increasing chloride conductance at GABA-Areceptors and attenuates glutamate excitatory response. It also altersmessenger RNA for GAD and GABA-A receptor subunits. In contrast,estrogen acts as a pro-convulsant by reducing chloride conductance andacting as an agonist at NMDA receptors in the CA1 region of thehippocampus. In another illustrative embodiment, one or more dimebolinsor pharmaceutically acceptable salts thereof is co-administered with oneor more of each of the foregoing AEDs.

In another illustrative embodiment, one or more dimebolins orpharmaceutically acceptable salts thereof is co-administered with one ormore GABA agonists, such as valproic acid, sodium valproate, divalproatesodium, sodium valproate modified release, tiagabine, and topiramate. Inanother embodiment, one or more dimebolins or pharmaceuticallyacceptable salts thereof is co-administered with sodium valproate. Inanother illustrative embodiment, one or more dimebolins orpharmaceutically acceptable salts thereof is co-administered with one ormore barbiturates. It is appreciated that ordinarily barbiturates havenot been extensively used due to the higher propensity for adverseevents observed with those drugs. Even so, but without being bound bytheory, when used as a co-therapy as described herein, it is appreciatedherein that lower doses may be used in conjunction with the one or moredimebolins or pharmaceutically acceptable salts thereof, leading to animproved therapeutic window.

In another embodiment, methods are described herein for treatingepilepsy and epileptic syndromes that include the step ofco-administering a therapeutically effective amount of one or moredimebolins or pharmaceutically acceptable salts thereof with one or moreinhibitors of HMG-CoA reductase, also referred to as statins.Illustrative statins include simvastatin, pravastatin, lovastatin,fluvastatin, atorvastatin, rosuvastatin or cerivastatin, or apharmaceutically acceptable salt thereof, including therapeuticallyeffective acid addition salt forms of any of the foregoing. In anotherembodiment, one or more dimebolins or pharmaceutically acceptable saltsthereof is co-administered with simvastatin. In another embodiment, oneor more dimebolins or pharmaceutically acceptable salts thereof isco-administered with simvastatin and sodium valproate. In anotherembodiment, methods are described herein that include the step ofco-administering a therapeutically effective amount of one or moredimebolins or pharmaceutically acceptable salts thereof with one or morestatins and one or more GABA transaminase inhibitors.

It is to be understood that in any of the embodiments described herein,the corresponding acid addition salt may be administered. Illustrativeacid salts may be formed from, but at not limited to, inorganic acidssuch as hydrohalic acids, including hydrochloric or hydrobromic acid;sulfuric; nitric; phosphoric, and the like acids; and organic acids suchas acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic,succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

The term “therapeutically effective amount” as used herein, refers tothat amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated. In addition, in those embodimentsdescribed herein drawn to combination therapy comprising administrationof one or more dimebolins or pharmaceutically acceptable salts thereofand one or more NMDA antagonists and/or one or more anti-epilepticdrugs, “therapeutically effective amount” refers to that amount of thecombination of agents taken together so that the combined effect elicitsthe desired biological or medicinal response. For example, thetherapeutically effective amount combinations or co-administeredcompounds and compositions, such as of dimebon and topiramate, dimebonand simvastatin, and the like, would illustratively be the amount ofdimebon and the amount of topiramate, or the amount of dimebon and theamount of the simvastatin, and the like that when taken together orsequentially have a combined effect that is therapeutically effective.Further, it is appreciated that in some embodiments of such methods thatinclude co-administration, the amount of dimebon, topiramate, and/orsimvastatin, and the like when taken individually may or may not betherapeutically effective.

In addition, in those embodiments described herein drawn to combinationtherapy, “therapeutically effective amount” refers to that amount of thecombination of agents taken together so that the combined effect elicitsthe desired biological or medicinal response. For example, thetherapeutically effective amount of one or more dimebolins and one ormore additional subtype selective or subtype specific NMDA antagonists,would be the amount of each component that when taken together orsequentially have a combined effect that is therapeutically effective.Further, it is appreciated that in some embodiments of such methods thatinclude co-administration, that co-administration amount of for exampleone or more dimebolins and one or more additional subtype selective orsubtype specific NMDA antagonists, when taken individually may or maynot be therapeutically effective.

It is also appreciated that the therapeutically effective amount,whether referring to monotherapy or combination therapy, isadvantageously selected with reference to any toxicity, or otherundesirable side effect, that might occur during administration of oneor more of the compounds described herein. Further, it is appreciatedthat the co-therapies described herein may allow for the administrationof lower doses of compounds that show such toxicity, or otherundesirable side effect, where those lower doses are below thresholds oftoxicity or lower in the therapeutic window than would otherwise beadministered in the absence of a cotherapy.

Accordingly, in another illustrative embodiment, the amounts of the oneor more NMDA receptor antagonists that are administered to the patientin the methods described herein are equal to or less than those that aregiven in conventional monotherapy using such NMDA receptor antagonists.In another illustrative embodiment, the amounts of the anti-epilepticdrugs that are administered to the patient in the methods described areequal to or less than those that are given in conventional monotherapyusing such anti-epileptic drugs.

In another illustrative embodiment where either or both of an NMDAreceptor antagonist and/or a anti-epileptic drug are co-administeredwith one or more dimebolins or pharmaceutically acceptable saltsthereof, co-administration includes dosing protocols where the two ormore compounds are given simultaneously or contemporaneously. It is tobe understood that co-administration is not limited to any particulartime frame. For example, dosing protocols where one or more dimebolinsor pharmaceutically acceptable salts thereof are given every other day,and the NMDA antagonist is given on the alternate days that thedimebolins are not given are included in the co-administration methodsdescribed herein.

In another embodiment, the therapeutically effective amount of the oneor more dimebolins is an amount capable of antagonizing NMDA receptorsand blocking calcium channels, such as L-type calcium channels. In onevariation, the therapeutically effective amount is capable of onlyblocking selected subtypes of NMDA receptors and blocking calciumchannels, such as L-type calcium channels. In another embodiment, thetherapeutically effective amount of the one or more dimebolins is anamount capable of inhibiting or blocking mitochondrial permeabilitytransition pores. In another embodiment, the therapeutically effectiveamount of the one or more dimebolins is an amount capable ofantagonizing NMDA receptors and blocking calcium channels, such asL-type calcium channels, and inhibiting or blocking mitochondrialpermeability transition pores.

As used herein, the term “composition” generally refers to any productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationsof the specified ingredients in the specified amounts. Illustratively,compositions may include one or more carriers, diluents, and/orexcipients. The compounds described herein may be formulated in atherapeutically effective amount in conventional dosage forms for themethods described herein, including one or more carriers, diluents,and/or excipients therefor. Such formulation compositions may beadministered by a wide variety of conventional routes for the methodsdescribed herein in a wide variety of dosage formats, utilizingart-recognized products. See generally, Remington's PharmaceuticalSciences, (16th ed. 1980). It is to be understood that the compositionsdescribed herein may be prepared from isolated compounds describedherein or from salts, solutions, hydrates, solvates, and other forms ofthe compounds described herein. It is also to be understood that thecompositions may be prepared from various amorphous, non-amorphous,partially crystalline, crystalline, and/or other morphological forms ofthe compounds described herein.

Optimal dosages and dosage regimens to be administered may be readilydetermined by those skilled in the art, and will vary with the mode ofadministration, the strength of the preparation and the advancement ofthe disease condition. In addition, factors associated with theparticular patient being treated, including patient's sex, age, weight,diet, physical activity, time of administration and concomitantdiseases, will result in the need to adjust dosages and/or regimens.

Examples of illustrative methods of administration include, but are notlimited to, oral (po), intravenous (iv), intramuscular (im),subcutaneous (sc), transdermal, and rectal. Compounds may also beadministered directly to the nervous system including, but not limitedto, intracerebral, intraventricular, intracerebroventricular,intrathecal, intracisternal, intraspinal and/or peri-spinal routes ofadministration by delivery via intracranial or intravertebral needlesand/or catheters with or without pump devices. It is to be understoodthat in the methods described herein that include co-administration ofone or more dimebolins or pharmaceutically acceptable salts thereof, theindividual components of a co-administration, or combination can beadministered by any suitable means, simultaneously, sequentially,separately or in a single pharmaceutical formulation. Where the one ormore dimebolins, the NMDA receptor antagonists and the anti-epilepticdrugs are administered in separate dosage forms, the number of dosagesadministered per day for each compound may be the same or different.Dimebolins, and optionally the NMDA receptor antagonists and/or theanti-epileptic drugs may be administered via the same or differentroutes of administration. Dimebolins, and optionally the NMDA receptorantagonists and/or the anti-epileptic drugs may be administeredaccording to simultaneous or alternating regimens, at the same ordifferent times during the course of the therapy, concurrently individed or single forms.

It is to be understood that a wide range of doses of one or moredimebolins or pharmaceutically acceptable salts thereof, either alone orin combination with another component, may be used in the methods andcompositions described herein. In addition, any suitable route ofadministration may be used in the methods described herein. In addition,any suitable formulation may be used for the compositions describedherein. In another illustrative embodiment, oral formulations of one ormore dimebolins or pharmaceutically acceptable salts thereof, eitheralone or in combination with another component, are described. Inanother illustrative embodiment, parenteral formulations of one or moredimebolins or pharmaceutically acceptable salts thereof, either alone orin combination with another component, are described.

In another embodiment, the methods described herein include the use ofcontrolled release and/or slow release formulations of the compoundsand/or combination of compounds described herein are described. It isappreciated that a controlled release and/or slow release formulation ofone or more dimebolins or pharmaceutically acceptable salts thereof, maybe advantageous for maintaining therapeutically effective blood levelsin between doses. In another embodiment, formulations suitable forparenteral administration are described herein, including formulationssuitable for pumps and or patches that may be adhered to or worn by apatient.

In another illustrative embodiment of the methods described herein, oneor more dimebolins or pharmaceutically acceptable salts thereof,described herein is illustratively administered to a patient orally inthe range from about 0.1 mg/kg to about 1 g/kg, from about 0.1 mg/kg toabout 1 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, from about 1mg/kg to about 10 mg/kg, from about 1 mg/kg to about 100 mg/kg, fromabout 1 mg/kg to about 200 mg/kg, from about 1 mg/kg to about 500 mg/kg,from about 1 mg/kg to about 1 g/kg, from about 10 mg/kg to about 100mg/kg, from about 10 mg/kg to about 200 mg/kg, from about 10 mg/kg toabout 500 mg/kg, from about 10 mg/kg to about 1 g/kg, from about 20mg/kg to about 50 mg/kg, from about 20 mg/kg to about 100 mg/kg, fromabout 20 mg/kg to about 200 mg/kg, from about 50 mg/kg to about 100mg/kg, from about 50 mg/kg to about 200 mg/kg, from about 100 mg/kg toabout 200 mg/kg, from about 100 mg/kg to about 500 mg/kg, or from about100 mg/kg to about 1 g/kg, where the dose corresponds to the total ofthe one or more dimebolins. It is also appreciated that when used incombination with other compounds described herein, such as with one ormore NMDA receptor antagonists, and/or one or more statins, and/or oneor more AEDs, the lower dose ranges may be illustratively used.

In another illustrative embodiment of the methods described herein, oneor more dimebolins or pharmaceutically acceptable salts thereof,described herein is illustratively administered to a patientparenterally in the range from about 0.1 mg/kg to about 1 g/kg, fromabout 0.1 mg/kg to about 1 mg/kg, from about 0.1 mg/kg to about 10mg/kg, from about 1 mg/kg to about 10 mg/kg, from about 1 mg/kg to about100 mg/kg, from about 1 mg/kg to about 200 mg/kg, from about 1 mg/kg toabout 500 mg/kg, from about 1 mg/kg to about 1 g/kg, from about 10 mg/kgto about 100 mg/kg, from about 10 mg/kg to about 200 mg/kg, from about10 mg/kg to about 500 mg/kg, from about 10 mg/kg to about 1 g/kg, fromabout 20 mg/kg to about 50 mg/kg, from about 20 mg/kg to about 100mg/kg, from about 20 mg/kg to about 200 mg/kg, from about 50 mg/kg toabout 100 mg/kg, from about 50 mg/kg to about 200 mg/kg, from about 100mg/kg to about 200 mg/kg, from about 100 mg/kg to about 500 mg/kg, orfrom about 100 mg/kg to about 1 g/kg, where the dose corresponds to thetotal of the one or more dimebolins. It is also appreciated that whenused in combination with other compounds described herein, such as withone or more NMDA receptor antagonists, and/or one or more statins,and/or one or more AEDs, the lower dose ranges may be illustrativelyused.

In another embodiment, when used alone or in combination, one or moredimebolins or pharmaceutically acceptable salts thereof, areadministered orally to a patient at a daily dose of 0.1, 0.5, 1.0, 2.0,or 5.0 mg/kg, corresponding to approximately, 6.0, 30, 60, 120, or 300mg for an average weight adult. Without limiting the foregoing, it isappreciated that such lower doses of dimebolins may be more applicableto an ongoing, or chronic therapy, designed for continuousadministration, rather than intermittent or acute administration.Accordingly, the daily dose may be divided and administered b.i.d.and/or t.i.d, although it is to be understood that q.d. dosing isdescribed herein.

It is to be understood that the illustrative doses described hereinrepresent daily doses, and may be therefore administered q.d., b.i.d.,t.i.d., and according to additional dosing protocols. In addition, it isto be understood that the doses may be single or divided.

It is appreciated that when used in combination with other compoundsdescribed herein, such as with one or more NMDA receptor antagonists,and/or one or more statins, and/or one or more AEDs, the lower doseranges may be illustratively used. It is further appreciated that asdescribed herein that one or more dimebolins or pharmaceuticallyacceptable salts thereof, may be efficacious within two or more distinctdosing windows. It has been discovered herein that because dimebolinsefficaciously operate via multiple mechanisms, dimebolins may beefficacious by a first mechanism of action at a lower dose, and alsoefficacious by a second mechanism of action at a higher dose.

Accordingly, also described herein are unitary dosage forms for oraladministration that include a low dose of one or more dimebolins orpharmaceutically acceptable salts thereof, such as 5 mg or 10 mg of atotal of one or more dimebolins, and one or more pharmaceuticallyacceptable carriers, diluents, or excipients. Illustratively, theunitary dosage forms are tablets or capsules.

In another embodiment, the methods described herein include the use oftablets for pediatric use. It is appreciated that pediatric dosages maynot be linearly related to adult doses on a mg/kg basis. Illustratively,pediatric doses of dimebolins are described herein, such as oral dosesthat include 2 mg, 2.5 mg, 3 mg, 5 mg, 10 mg, or 15 mg, each of whichmay be administered q.d., b.i.d., t.i.d., or according to additionaldosing protocols, and be in a single or divided unitary dose format.

In one variation of each of the foregoing embodiments, the one or moredimebolins or pharmaceutically acceptable salts thereof, areadministered t.i.d.

In another embodiment, chronic dosing protocols are described for themethods described herein. In one aspect, one or more dimebolins orpharmaceutically acceptable salts thereof, is administered to a patientin need of relief from epilepsy on a continuous basis whether or not thepatient is showing any signs or symptoms of epilepsy. Illustratively,the dose administered is selected from the lower ranges of dosingdescribed herein. In another embodiment, acute dosing protocols aredescribed for the methods described herein. In one aspect, one or moredimebolins or pharmaceutically acceptable salts thereof, is administeredto a patient in need of relief from epilepsy on an intermittent basis,as determined by recent or anticipated signs or symptoms of epilepsy.Illustratively, the dose administered is selected from the higher rangesof dosing described herein.

In another embodiment, when used alone or in combination, one or moredimebolins or pharmaceutically acceptable salts thereof, areadministered intravenously to a patient at a daily dose of 5.0, 10, 15,20, 25, or 30 mg/kg, corresponding to approximately, 300, 600, 900,1200, 1500, or 1800 mg for an average weight adult. Without limiting theforegoing, it is appreciated that such higher doses of dimebolins may bemore applicable to an acute therapy, such as in a rescue or emergencysituation, rather than an ongoing, or chronic therapy.

In another embodiment, the methods described herein include a titrationstep where the dose is gradually increased over a predetermined timeperiod, such as a two step protocol for adults as follows: 2 mg thricedaily for 7 days, then 5 mg thrice daily, 5 mg thrice daily for 7 days,then 10 mg thrice daily, or 10 mg thrice daily for 7 days, then 20 mgthrice daily.

In another embodiment, process for making pharmaceutical compositionsare described herein. The processes include the step of adapting the oneor more dimebolins and the one or more NMDA receptor antagonists, orpharmaceutically acceptable salts of the foregoing, forco-administration. In another embodiment, the processes include the stepof adapting the one or more dimebolins and the one or more otheranti-epileptic drugs, or pharmaceutically acceptable salts of theforegoing, for co-administration. In another embodiment, the processesinclude the step of adapting the one or more dimebolins, the one or moreother anti-epileptic drugs, and the one or more NMDA receptorantagonists, or pharmaceutically acceptable salts of the foregoing, forco-administration.

In another embodiment, pharmaceutical composition packages are describedherein. In one embodiment, the package includes a therapeuticallyeffective amount of one or more dimebolins and a therapeuticallyeffective amount of one or more NMDA receptor antagonists, orpharmaceutically acceptable salts of the foregoing, each adapted forco-administration. In another embodiment, the package includes atherapeutically effective amount of one or more dimebolins and atherapeutically effective amount of one or more other anti-epilepticdrugs, or pharmaceutically acceptable salts of the foregoing; eachadapted for co-administration. In another embodiment, the packageincludes a therapeutically effective amount of one or more dimebolins, atherapeutically effective amount of one or more NMDA receptorantagonists, and a therapeutically effective amount of one or more NMDAreceptor antagonists, or pharmaceutically acceptable salts of theforegoing, each adapted for co-administration.

It is to be understood that in each of the foregoing embodiments of themethods and medicaments described herein, any one or more of thedimebolins may be included therein. For example, in each of theforegoing embodiments of the methods and medicaments described herein,the dimebolin may be dimebon (dimebolin hydrochloride), or otherpharmaceutically acceptable salt thereof.

The effective use of the methods described herein for treating orameliorating one or more effects of a epilepsy or epileptic syndromesusing one or more compounds described herein may be based upon animalmodels, such as murine and rabbit models. For example, it is understoodthat epilepsy and/or epileptic syndromes in humans are characterized bya loss of function, and/or the development of symptoms, each of whichmay be elicited in animals, such as mice and rabbits, and othersurrogate test animals. Illustrative models that may be used to evaluatethe methods of treatment and the pharmaceutical compositions describedherein to determine the therapeutically effective amounts describedherein, include the rabbit anti-GluR3 antibody model, rat global hypoxiamodel, rat hyperthermia-induced model, baboon or cat GABA withdrawal,tetanus toxin model, mouse cystatin B-deficient model, beagle or ratlateral fluid—percussion injury model, baboon, chicken or rat/hot watermodel, rat or mouse GEPRs, DBA/2 mouse model, mouse EL mouse model, rattish mutation model, mouse GABA receptor b3 knockout model,TNAP-deficient mouse model (BALBc mice), macular mutant mouse model,twitcher mouse model, mouse ethanol withdrawal model, the JNK3homozygous (−/−) knockout mouse model, and the mouse, rat, or rabbitcocaine-induced model, the descriptions are which are described bySarkisian, Epilepsy & Behavior 2, 201-216 (2001), and referencestherein, the disclosure of which is incorporated herein by reference.

The following examples further illustrate specific embodiments of theinvention; however, the following illustrative examples should not beinterpreted in any way to are to limit invention.

EXAMPLES Example Kainic Acid or Pilocarpine Induced Kindling Model inRats

One or more dimebolins are shown to be efficacious in the rat. Briefly,compounds described herein are administered to male CD rats at 10 mg/kgintravenously through a tail vein catheter, followed immediately by a 30mg/kg subcutaneous injection. Vehicle controls receive the sameinjection volumes of the PPCES vehicle alone. Thirty minutes later,animals are given a 1-mg/kg i.p. injection of kainic acid in normalsaline solution (a dose of kainic acid that has been previously reportedto induce a seizure syndrome in rats, Maj et al., Eur. J. Pharm. 359:2732, 1992). Seizure behavior is monitored for 4 hours following kainicacid injection. Behaviors are assessed based on the following cumulativescoring system: 1 pt.=arrest of motion; 2 pts.=myoclonic jerks of thehead and neck (moderate); 3 pts.=unilateral or bilateral forelimb clonicactivity; 4 pts.=whole body clonus; 5 pts.=clonic-tonic seizures; 6pts.=status epilepticus (see also Mathis and Ungerer, Exp. Brain Res.88:277 282, 1992; Rong et al., Proc. Natl. Acad. Sci. USA 96:9897 9902,1999; Yang et al., Nature 389:865 870, 1997, Muller-Schwarz et al.,Neuroreport, vol. 10, No. 7, 1999, pp. 1517-1522; Ebert et al. Epilepsia2002, 43 Suppl 5, 86-95; Tober et al. European Journal of Pharmacology1996, 303, 163-169; Clifford et al, “Effect of anti-convulsant drugs onkainic acid induced epileptiform activity,” Exp. Neurol. 76: 156(1982)).

Example Chronic Anticonvulsant Activity Using the Kainic Acid SeizureTest in Rat

Dimebolins, including the compounds described herein, are shown to beefficacious in the rat kainic acid anticonvulsant activity model. It isappreciated that this model, though general, may also most closelycorrespond to and/or be more predictive of temporal lobe epilepsy foundin humans. However, it is to be understood that this model is a generalsurrogate for all types of epilepsy.

Male Wistar rats (such as Male Rj: Wistar (Han) rats, weighing 180-280 gat the day of testing, from Elevage Janvier, 53940 Le Genest-Saint-Isle,France) are placed in groups of 4-5 in macrolon cages (41×25×18 cm or44×28×19 cm) on wood litter (Litalabo-SPPS, 95100 Argenteuil, France),with free access to food and water until tested, and maintained underartificial lighting (12 hours) between 7:00 and 19:00 in a controlledambient temperature of about 21° C., and relative humidity between30-80%. Animals are acclimatized to laboratory conditions for least 3days. Animals surviving the experiments are sacrificed at the end of theexperiments by exposure to a mixture of O₂/CO₂ (20%/80%) followed byCO₂.

Dimebon, or an analog or derivative thereof, either alone or incombination with one or more other compounds as described herein, isevaluated at 3 doses (e.g. 1, 3, and 10 mg/kg), administered i.p. oncedaily for seven days, with a administration volume of 5 mL/kg. The lastadministration (7th) is injected 30 minutes prior to kainic acidadministration, and compared with a vehicle control group. The testarticle (single compound or combination) is prepared in 0.2% HPMC inphysiological saline as follows: The test article is tested forsolubility by cold stirring of the highest intended dose for 10 minutesin physiological saline. If soluble, physiological saline serves asvehicle, and doses are prepared W/V (stock) and then V/V (serialdilutions). Preparations may be made freshly for each day ofadministration and precautions may be taken to preserve the homogeneityof suspensions (if applicable) during the period of administration.

Diazepam (4 mg/kg i.p.) is administered in 0.2% HPMC in physiologicalsaline 30 minutes prior to KA, and is used as reference substance(positive control). Kainic acid (12 mg/kg i.p.) dissolved inphysiological saline is administered 30 minutes following the 7thadministration of test article, diazepam, or vehicle control. Additionaldetails are described in Ben-Ari et al, Neuroscience, 6, 1361-1391, 1981for detecting anticonvulsant activity related to a glutamatergicmechanism.

Animals are injected with kainic acid (12 mg/kg i.p.). The occurrencesof the following symptoms are noted over a 120 minute period afterkainic acid injection: wet-shakes, rearings, and rearings with forelimbclonus. The primary outcome measure will be a binary measure of whethereach rat displays forelimb clonus following KA administration (0: no; 1:yes). In addition, the latencies to the first appearance of the symptomsare measured and the number of forelimb clonus are counted. The numberof forelimb clonus episodes per time interval starting from the firstoccurrence of forelimb clonus will be considered regarding the severityscale. 10 animals are studied per group. The test is performed blind.Quantitative data is analyzed by comparing treated groups with vehiclecontrol using unpaired Student's t tests. Quantal data is analyzed bycomparing treated groups with vehicle control using Fisher's ExactProbability tests. The results for dimebon are shown in the followingtable,

Rearings with Forelimb Forelimb Wet-shakes Rearings Clonus ClonusCompound^((a)) Presence^((b)) Latency^((c)) Presence Latency PresenceLatency No.^((d)) Vehicle 10 2456 9 3959 10 5038 2.8 (197)^((e)) (518)(310) (0.5)^((f)) Dimebon  1  8 ^(NS) 3615 ^(NS) 6 ^(NS) 4896 ^(NS)  7^(NS) 6009 * 1.9 ^(NS) −20%^((g)) (613) −33% (653) −30% (321) (0.5)  t =1.8  t = 1.1  t = 2.2  t = 1.2 p = 0.10 p = 0.28 p = 0.043 p = 0.25+47%^((h)) +24% +19% −32%  3 10 ^(NS) 2666 ^(NS) 9 ^(NS) 4134 ^(NS)  9^(NS) 5366 ^(NS) 2.5 ^(NS) (176) (391) (416) (0.6)  t = 0.79  t = 0.27 t = 0.63  t = 0.37  0% p = 0.44  0% p = 0.79 −10% p = 0.54 p = 0.71 +9%  +4%  +7% −11% 10 10 ^(NS) 2865 ^(NS) 8 ^(NS) 4526 ^(NS)  9 ^(NS)5410 ^(NS) 2.3 ^(NS) (235) (522) (253) (0.4)  t = 1.3  t = 0.77  t =0.93  t = 0.77  0% p = 0.20 −11% p = 0.45 −10% p = 0.37 p = 0.45 +17%+14%  +7% −18% Diazepam  4  9 ^(NS) 3753 * 9 ^(NS) 4282 ^(NS)  4 * 6841*** 0.6 ** (405) (427) (200) (0.3)  t = 2.9  t = 0.48  t = 4.9  t = 3.8−10% p = 0.013  0% p = 0.64 −60% p = 0.0002 p = 0.0020 +53%  +8% +36%−79% ^((a))Except for vehicle control, dose amount in mg/kg administeredi.p. once daily on each of days 1 to 6, then 30 min before kainic acidadministration on day 7; ^((b))Presence observed out of 10 test animals;significance determined with Fisher's Exact test, ^(NS) = notsignificant, * = p < 0.05; ^((c))average time in seconds calculated fromall animals in group; significance determined with Student's t test(unequal variances), ^(NS) = not significant, * = p < 0.05, ** = p <0.01, *** = p < 0.001; ^((d))average number observed calculated from allanimals in group; ±s.e.m. in parenthesis; significance determined withStudent's t test (unequal variances), ^(NS) = not significant, * = p <0.05, ** = p < 0.01, *** = p, 0.001; ^((e))±s.e.m.; ^((f))±s.e.m.;^((g))% change from vehicle; ^((h))% change from vehicle.

Example Acute Anticonvulsant Activity Using the Kainic Acid Seizure Testin Rat

Dimebon, or an analog or derivative thereof, including the compoundsdescribed herein, is shown to be efficacious in the rat kainic acidanticonvulsant activity model. The prior Example is followed with theexception that the test article, dimebon, or an analog or derivativethereof, either alone or in combination with one or more other compoundsas described herein, is evaluated at a single dose of 100 mg/kg,administered i.p., with a administration volume of 5 mL/kg, 60 minutesprior to kainic acid administration, and compared with a vehicle controlgroup. The 100 mg/kg formulation is prepared in 0.2% HPMC inphysiological saline. The results for dimebon are shown in the followingtable.

Rearings with Forelimb Forelimb Wet-shakes Rearings Clonus ClonusCompound^((a)) Presence^((b)) Latency^((c)) Presence Latency PresenceLatency No.^((d)) Dimebon 100 5 ^(NS) 4394 ^(NS) 2 * 6197 * 6 ^(NS) 4546^(NS) 1.3 ^(NS) −50%^((e)) (836) −78% (707) −40% (866) (0.5)  t = 2.3  t= 2.6  t = 0.54  t = 2.1 p = 0.055 p = 0.023 p = 0.60 p = 0.057+79%^((f)) +57% −10% −54% ^((a))Except for vehicle control, dose amountin mg/kg administered i.p. once daily on each of days 1 to 6, then 30min before kainic acid administration on day 7; ^((b))Presence observedout of 10 test animals; significance determined with Fisher's Exacttest, ^(NS) = not significant, * = p < 0.05; ^((c))average time inseconds calculated from all animals in group; significance determinedwith Student's t test (unequal variances), ^(NS) = not significant, * =p < 0.05, ** = p < 0.01, *** = p < 0.001; ^((d))average number observedcalculated from all animals in group; ±s.e.m. in parenthesis;significance determined with Student's t test (unequal variances), ^(NS)= not significant, * = p < 0.05, ** = p < 0.01, *** = p, 0.001; ^((e))%change from vehicle; ^((f))%change from vehicle.

Example

One or more dimebolins, such as Dimebon (20 mg total) is administeredthree times daily to a patient suffering from or in need of relief fromepilepsy, or an epileptic condition. Illustratively, the dimebon in theform of tablets (comprising 10 mg or 20 mg of dimebon, 30 mg of lactose,and 5 mg of magnesium stearate) for oral administration. The duration oftreatment in this and other examples described herein is determinedaccording to the progression of epilepsy in each individual patient anddose adjustments are made accordingly. Treatment efficacy in this andother examples described herein is monitored by self-reporting and theresults of treatment are evaluated statistically using Student's t-testand/or Fisher's “Fi” criterion.

Example

One or more dimebolins, such as Dimebon (25 mg total) is administeredthree times daily to a patient suffering from or in need of relief fromepilepsy, or an epileptic condition. Illustratively, the dimebon in theform of tablets (comprising 12.5 mg or 25 mg of dimebon, 30 mg oflactose, and 5 mg of magnesium stearate) for oral administration. Theduration of treatment in this and other examples described herein isdetermined according to the progression of epilepsy in each individualpatient and dose adjustments are made accordingly. Treatment efficacy inthis and other examples described herein is monitored by self-reportingand the results of treatment are evaluated statistically using Student'st-test and/or Fisher's “Fi” criterion.

Example

One or more dimebolins, such as Dimebon (30 mg total) is administeredthree times daily to a patient suffering from or in need of relief fromepilepsy, or an epileptic condition. Illustratively, the dimebon in theform of tablets (comprising 15 mg or 30 mg of dimebon, 45 mg of lactose,and 7.5 mg of magnesium stearate) for oral administration. The durationof treatment in this and other examples described herein is determinedaccording to the progression of epilepsy in each individual patient anddose adjustments are made accordingly. Treatment efficacy in this andother examples described herein is monitored by self-reporting and theresults of treatment are evaluated statistically using Student's t-testand/or Fisher's “Fi” criterion.

Example

One or more dimebolins, such as Dimebon (30 mg total) is administeredtwice daily to a patient suffering from or in need of relief fromepilepsy, or an epileptic condition. Illustratively, the dimebon in theform of tablets (comprising 15 mg or 30 mg of dimebon, 45 mg of lactose,and 7.5 mg of magnesium stearate) for oral administration. The durationof treatment in this and other examples described herein is determinedaccording to the progression of epilepsy in each individual patient anddose adjustments are made accordingly. Treatment efficacy in this andother examples described herein is monitored by self-reporting and theresults of treatment are evaluated statistically using Student's t-testand/or Fisher's “Fi” criterion.

Example

One or more dimebolins, such as Dimebon (40 mg total) is administeredtwice daily to a patient suffering from or in need of relief fromepilepsy, or an epileptic condition. Illustratively, the dimebon in theform of tablets (comprising 20 mg or 40 mg of dimebon, 60 mg of lactose,and 10 mg of magnesium stearate) for oral administration. The durationof treatment in this and other examples described herein is determinedaccording to the progression of epilepsy in each individual patient anddose adjustments are made accordingly. Treatment efficacy in this andother examples described herein is monitored by self-reporting and theresults of treatment are evaluated statistically using Student's t-testand/or Fisher's “Fi” criterion.

Example

One or more dimebolins, such as Dimebon (50 mg total) is administeredtwice daily to a patient suffering from or in need of relief fromepilepsy, or an epileptic condition. Illustratively, the dimebon in theform of tablets (comprising 25 mg or 50 mg of dimebon, 60 mg of lactose,and 10 mg of magnesium stearate) for oral administration. The durationof treatment in this and other examples described herein is determinedaccording to the progression of epilepsy in each individual patient anddose adjustments are made accordingly. Treatment efficacy in this andother examples described herein is monitored by self-reporting and theresults of treatment are evaluated statistically using Student's t-testand/or Fisher's “Fi” criterion.

Example

Dimebon is administered as described herein, such as oral administrationof 20 mg, 25 mg, or 30 mg, three times daily, and co-administered withoral simvastatin (20 mg tablet, Merck & Co Inc) two times daily.

Example

Dimebon is administered as described herein, such as oral administrationof 20 mg, 25 mg, or 30 mg, three times daily, and co-administered withoral sodium valproate tables (500 mg, Sanofi-Aventis) three times daily.

Example

Dimebon is administered as described herein, such as oral administrationof 20 mg, 25 mg, or 30 mg, three times daily, to a patient diagnosedwith Juvenile Myoclonic Epilepsy, and co-administered with oralsimvastatin (20 mg tablet, Merck & Co Inc) two times daily, andco-administered with oral sodium valproate (500 mg tablet,Sanofi-Aventis) three times daily.

Example

Dimebon is administered as described herein, such as oral administrationof 20 mg, 25 mg, or 30 mg, three times daily, to a patient diagnosedwith juvenile typical absence epilepsy, and co-administered with 20 mgoral memantine (10 mg, twice daily). In one variation, treatment isstarted with 5 mg (once daily) of dimebon (half a tablet in the morning)during the 1st week, 10 mg per day (half a tablet twice a day) in the2nd week, 15 mg per day (one tablet in the morning and half a tablet inthe afternoon or evening) in the 3rd week, and then the recommendedmaintenance dose of 20 mg per day (one tablet twice a day) in the 4thweek and beyond. In another variation, treatment is started with 5 mg(once daily, half a tablet in the morning) with memantine during the 1stweek, 10 mg per day (half a tablet twice a day) in the 2nd week, 15 mgper day (one tablet in the morning and half a tablet in the afternoon orevening) in the 3rd week, and then the recommended maintenance dose of20 mg per day (one tablet twice a day) in the 4th week and beyond.

Example

Dimebon is administered as described herein, such as oral administrationof 20 mg, 25 mg, or 30 mg, three times daily, to a patient diagnosedwith juvenile absence epilepsy, and co-administered with oralethosuximide (250 mg tablet, Pfizer) three times daily.

Example

Dimebon is administered as described herein, such as oral administrationof 20 mg, 25 mg, or 30 mg, three times daily, to a patient diagnosedwith juvenile absence epilepsy, and co-administered with oral sodiumvalproate tables (500 mg, Sanofi-Aventis) two times daily.

Example

Dimebon is administered as described herein, such as oral administrationof 20 mg, 25 mg, or 30 mg, three times daily, to a patient diagnosedwith complex partial seizures, and co-administered with oraloxcarbamazepine (600 mg tablet) three times daily.

Example

Dimebon is administered as described herein, such as oral administrationof 2×25, 2×50, or 2×100 mg three times daily, to a patient diagnosedwith juvenile typical absence epilepsy, and co-administered with 20 mgoral memantine (10 mg, twice daily). In one variation, treatment isstarted with 25 mg (once daily) of dimebon during the 1st week, 2×25 mgper day in the 2nd week, 3×25 mg per day in the 3rd week, and then therecommended maintenance dose of 2×50 mg per day in the 4th week andbeyond. In another variation, treatment is started with 25 mg (oncedaily) with memantine during the 1st week, 2×25 mg per day in the 2ndweek, 3×25 mg per day in the 3rd week, and then the recommendedmaintenance dose of 2×50 mg per day in the 4th week and beyond.

Example

Dimebon is administered as described herein, such as oral administrationof 100 mg, three times daily, to a patient diagnosed with juvenileabsence epilepsy, and co-administered with oral ethosuximide (250 mgtablet, Pfizer) three times daily.

Example

Dimebon is administered as described herein, such as oral administrationof 100 mg, three times daily, to a patient diagnosed with juvenileabsence epilepsy, and co-administered with oral sodium valproate tables(500 mg, Sanofi-Aventis) two times daily.

Example

Dimebon is administered as described herein, such as oral administrationof 100 mg, three times daily, to a patient diagnosed with complexpartial seizures, and co-administered with oral oxcarbamazepine (600 mgtablet) three times daily.

What is claimed is:
 1. A method for treating a disease selected from thegroup consisting of epilepsy and epileptic syndromes in a patient inneed of relief, the method comprising the step of administering to thepatient a therapeutically effective amount of one or more dimebolins ora pharmaceutically acceptable salts thereof.
 2. The method of claim 1further comprising the step of co-administering a therapeuticallyeffective amount of one or more NMDA receptor antagonists orpharmaceutically acceptable salts thereof.
 3. The method of claim 2wherein at least one of the NMDA receptor antagonists is selected fromthe group consisting of riluzole, memantine, and dextromethorphan, andpharmaceutically acceptable salts thereof.
 4. The method of claim 1further comprising the step of co-administering a therapeuticallyeffective amount of one or more other anti-epileptic drugs, orpharmaceutically acceptable salts thereof.
 5. The method of claim 4wherein the other anti-epileptic drug is a sodium channel blocker
 6. Themethod of claim 1 further comprising the step of co-administering atherapeutically effective amount of one or more statins, orpharmaceutically acceptable salts thereof.
 7. The method of claim 1further comprising the step of co-administering a therapeuticallyeffective amount of one or more AMPA antagonists, or pharmaceuticallyacceptable salts thereof.
 8. The method of any one of claims 1 to 7wherein the disease is a generalized epilepsy.
 9. The method of claim 8wherein the generalized epilepsy is tonic-clonic epilepsy.
 10. Themethod of claim 8 wherein the generalized epilepsy is clonic epilepsy.11. The method of claim 10 wherein the clonic epilepsy has tonicfeatures.
 12. The method of claim 10 wherein the clonic epilepsy doesnot have has tonic features.
 13. The method of claim 8 wherein thegeneralized epilepsy is typical absence epilepsy.
 14. The method ofclaim 8 wherein the generalized epilepsy is atypical absence epilepsy.15. The method of claim 8 wherein the generalized epilepsy is myoclonicabsence epilepsy.
 16. The method of claim 8 wherein the generalizedepilepsy is tonic epilepsy.
 17. The method of claim 8 wherein thegeneralized epilepsy is myoclonic epilepsy.
 18. The method of claim 8wherein the generalized epilepsy is massive bilateral myoclonus.
 19. Themethod of claim 8 wherein the generalized epilepsy is an eyelidmyoclonia.
 20. The method of claim 19 wherein the eyelid myclonia isaccompanied by absence seizures.
 21. The method of claim 19 wherein theeyelid myclonia is not accompanied by absence seizures.
 22. The methodof claim 8 wherein the generalized epilepsy is myclonic-atonic epilepsy.23. The method of claim 8 wherein the generalized epilepsy is negativemyoclonus.
 24. The method of claim 8 wherein the generalized epilepsy isatonic epilepsy.
 25. The method of claim 8 wherein the generalizedepilepsy is reflex epilepsy.
 26. The method of any one of claims 1 to 7wherein the disease is a focal epilepsy.
 27. The method of claim 26wherein the focal epilepsy is focal sensory epilepsy.
 28. The method ofclaim 27 wherein the focal sensory epilepsy presents with elementarysensory symptoms.
 29. The method of claim 27 wherein the focal sensoryepilepsy presents with experiential sensory symptoms.
 30. The method ofclaim 27 wherein the focal epilepsy is focal motor epilepsy.
 31. Themethod of claim 30 wherein the focal motor epilepsy presents withelementary clonic motor signs.
 32. The method of claim 30 wherein thefocal motor epilepsy presents with asymmetrical tonic motor seizures.33. The method of claim 30 wherein the focal motor epilepsy presentswith typical automatisms.
 34. The method of claim 30 wherein the focalmotor epilepsy presents with hyperkinetic automatisms.
 35. The method ofclaim 30 wherein the focal motor epilepsy presents with focal negativemyoclonus.
 36. The method of claim 30 wherein the focal motor epilepsypresents with inhibitory motor seizures.
 37. The method of claim 26wherein the focal epilepsy is gelastic epilepsy.
 38. The method of claim26 wherein the focal epilepsy is hemiclonic epilepsy.
 39. The method ofclaim 26 wherein the focal epilepsy is secondarily generalized epilepsy.40. The method of claim 26 wherein the focal epilepsy is reflex seizuresin focal epilepsy syndromes.
 41. A pharmaceutical composition comprisinga therapeutically effective amount of one or more dimebolins and atherapeutically effective amount of one or more NMDA receptorantagonists, or pharmaceutically acceptable salts of the foregoing; andone or more pharmaceutically acceptable carriers, diluents, orexcipients therefor, and combinations thereof; wherein the one or moredimebolins and the one or more NMDA receptor antagonists are adapted tobe co-administered in the method of any one of claims 1 to
 7. 42. Apharmaceutical composition comprising a therapeutically effective amountof one or more dimebolins and a therapeutically effective amount of oneor more other anti-epileptic drugs, or pharmaceutically acceptable saltsof the foregoing; and one or more pharmaceutically acceptable carriers,diluents, and excepients therefor, and combinations thereof; wherein theone or more dimebolins and one or more anti-epileptic drugs are adaptedto be co-administered in the method of any one of claims 1 to
 7. 43. Thepharmaceutical composition of claim 42 further comprising atherapeutically effective amount of one or more NMDA receptorantagonists or pharmaceutically acceptable salts thereof, wherein theone or more dimebolins, the one or more other anti-epileptic drugs, andthe one or more NMDA receptor antagonists are adapted to beco-administered in the method of any one of claims 1 to 7.